Latest ADI Awards Provide $7.5 Million to Study Brain Cell Growth and Development

Latest ADI Awards Provide $7.5 Million to Study Brain Cell Growth and Development

Frontier researchers receive grants to further advance early-stage research in the field of neuronal maturation

SEATTLE, WASH. — April 30, 2015 — The Paul G. Allen Family Foundation announced today the award of Allen Distinguished Investigator (ADI) grants to six groups of researchers with projects at the frontier of one of the most challenging roadblocks in neuroscience: growing mature human brain cells in the laboratory. The projects are funded at a total of $7.5 million over three years.

“This new cohort of Allen Distinguished Investigators and their research is especially significant because the field of neuronal maturation is at the leading edge of bioscience,” says Tom Skalak, Ph.D., Executive Director for Science and Technology for the Paul G. Allen Family Foundation. “The awardees’ broad talents and areas of expertise are what we need to explore this beckoning undiscovered territory.”

Studying human brain cells is one of the most promising ways to better understand the function of the healthy brain as well as provide insight into the development of diseases like Alzheimer’s and Parkinson’s. “Despite this potential, progress has been limited by a major gap in our scientific understanding,” comments Skalak. It typically takes more than a year to develop cells that come close to resembling fully mature neurons, and even then, yield is often low and full maturity has not been reached.

The six projects chosen to receive ADI grants in the field of neuronal maturation all tackle one or more of these challenges in bold new ways, including using innovative technologies and novel points of view.

Research in neuronal maturation is fundamental to many aspects of neuroscience research, including the work being conducted at the Allen Institute for Brain Science. The projects chosen for ADI grants complement the work at the Allen Institute and neuroscience as a whole.

“Our work at the Allen Institute for Brain Science has revealed that the field of neuronal maturation is in great need of exploration,” says Christof Koch, Ph.D., Chief Scientific Officer at the Allen Institute for Brain Science. “This inspiring cohort of national innovators identified by the Foundation will make important advances using their own ideas, and we expect the resulting insights will in turn accelerate the Institute’s work to understand neural function and human cognition itself.”

The Foundation seeks to open new frontiers in science, and the ADI program supports early-stage research with the potential to re-invent entire fields. Successful neuronal maturation would have widespread impact on the field of neuroscience, including changing how researchers study the healthy brain as well as how they seek treatments for diseases like autism, Alzheimer’s and Parkinson’s.

About the ADI Recipients

Allen Distinguished Investigators are passionate thought leaders, explorers, and innovators who seek world-changing breakthroughs. With grants between $1 million and $1.5 million each, the Foundation provides these scientists with enough funds to produce momentum in their respective fields. The new ADI recipients are:

One of the major obstacles to using human stem cells in the laboratory is that even the best protocols yield immature or inconsistent cells. Geschwind and Horvath are using mathematical predictions to identify factors that drive neuronal maturation in the human brain but that are absent in neurons grown from stem cells in cell culture. They will use these factors to create more stable cultures that are more similar to functioning neurons in the brain. They have also identified an aging clock based on genetic measurements from thousands of cells and tissues, and will use similar methods to mimic the effects of aging in the laboratory.

Feng Zhang, Massachusetts Institute of Technology ($1 million)

Understanding the biological mechanisms of neuronal differentiation and maturation is fundamental to rapidly replicating the diversity of cells in the human brain. Zhang’s project focuses on developing a highly scalable genomic engineering system that can reliably evaluate the genetic activity that leads to differentiated and matured cells, as well as produce differentiated and matured cells by modifying this genetic activity. He will apply the transcriptome analysis and powerful perturbation systems previously developed in his lab to study and later generate a number of human neuronal cell types relevant to neurological disorders.

Jeffrey Macklis, Harvard University ($1.5 million)

Macklis’ project has four proposed aims. The first is to develop a molecular-DNA "flight data recorder" inserted into individual cells, both to observe the rare cells that undergo remarkably appropriate partial maturation, and those that becomes stalled, confused, delayed, or immature. The second aim builds molecular timekeepers in order to better understand maturation time for individual cells. The third aim develops entirely novel synthetic biology technology to discover biological interactions during development that neurons may require to sequence through maturation “checkpoints.” The fourth aim develops first-in-field analysis of neuronal diversity and maturation at a deep level, in order to understand the basis of brain wiring and circuitry.

Erik Ullian and David Rowitch, University of California, San Francisco ($1 million)

Astrocytes are the most abundant cell type in the human brain, providing signals that are essential for all aspects of neuronal function and survival. But just as no two neurons are the same, astrocytes are incredibly diverse and specialized. Different types of astrocytes can provide different kinds of support and signals to the neurons they surround. In this proposal, Ullian and Rowitch will test whether the signals from different types of human astrocytes are necessary for the proper maturation and function of human iPSC-derived neurons. Their previous work in mouse models indicates that generating astrocytes that are matched to their partner neurons will be essential to studying and understanding human neuronal function in both health and disease.

William Lowry and Kathrin Plath, University of California, Los Angeles ($1.3 million)

Another obstacle to creating useful pluripotent stem cells is purity, since it is nearly impossible to create pure populations of particular subtypes of neurons or glia, and those that are generated are more similar to those found during early fetal development as opposed to the cells that are needed clinically. Lowry and Plath have devised a model system to isolate and identify very specific types of neurons, which they can use to create neurons that are more like those found in the adult nervous system. These particular types of neurons are thought to be dysfunctional in various disorders including autism, Alzheimer’s and schizophrenia, so increased knowledge of these specific neurons could dramatically facilitate the study and eventual treatment of these devastating disorders.

This project will address two major roadblocks in neuronal maturation—diversity of cells in the brain and the developmental “clock”—in the context of the retina. The retina is ideal for these studies because it is a self-contained part of the nervous system with known cell types and stereotypic connections that have well-defined functions. The project will determine how closely the neural circuitry in a stem cell-derived retina resembles its normal in vivo counterpart, and will also investigate whether small RNAs, called microRNAs, control the developmental clock of maturation in the retina. Understanding the function of microRNAs in the retina, which appear to control the clock of maturation throughout our lives, will lead to better models of neurological diseases of aging and provide a basis for building a functional nervous system in the laboratory.